Influenza is an infectious disease of respiratory track that affects millions of people every year. Since antibodies (Abs) play important roles in protection against influenza virus, preventive vaccination has been the most efficient measure of influenza control. While hemagglutinin (HA) is the main target for virus-neutralizing Abs, it mediates virus entry into cells at two steps (Non-patent literature 1). First, HA binds to the cell receptor, sialic acid. After internalization of viruses by endocytosis, HA undergoes a drastic conformational change induced by low pH. It has been shown that neutralizing Abs have one of the following activities: prevention of binding reaction between HA and sialic acid (Non-patent literature 2) and prevention of low-pH-induced conformational change of HA (Non-patent literature 3). The former (hereinafter referred to as “1st type neutralizing Abs”) binds to the site near sialic acid-binding pocket on the globular head in HA, and the latter binds to the stem region of HA. Since the dominant immune response is the first type, and mutations can be easily introduced into the target sites without losing the receptor-binding activity, variant viruses that have acquired resistance to these Abs become dominant and cause annual epidemics. Historically, it was long believed that all effective neutralizing Abs are the first type, and therefore, vaccine strains should have been changed almost every year in order to remain effective. As long as the type of vaccine strain well matches up to that of circulating virus, vaccination is effective for preventing virus infection.
Mode of response against infection of influenza virus is very heterogeneous among human population. For example, there are many persons who had suffered from influenza several times in their childhood but never suffered afterwards without vaccination. In 2009, a swine-origin H1N1 influenza virus (S-OIV) emerged and rapidly spread among human population, resulting in its classification as the first pandemic in the 21st century (Non-patent literature 4). It has been generally believed that humans lack immunity to the newly appearing influenza virus at the outbreak of pandemic because they are naive to the virus. In the case of S-OIV, however, long-lived memory B cells that produce broadly neutralizing Abs not only against seasonal H1N1 viruses but also S-OIV are found in many of the elderly (Non-patent literature 5 to 7).